Amidine compounds

ABSTRACT

Amidine derivatives of opioids of the formula YN—X—(NH)n-C(═NR)—R′ in which YN is a morphine-like opioid radical; X is a direct bond, a substituted or unsubstituted, branched, straight-chained or cyclic alkylene having from 1 to 6 carbon atoms, optionally containing one or two heteroatoms in the alkyl chain, or an optionally substituted, branched or straight-chained alkenylene having from 4 to 10 carbon atoms; R and R′ are independently hydrogen, alkyl, substituted alkyl, alkene, substituted alkene, alkyne, substituted alkyne, aryl, substituted aryl, heterocycle, substituted hetercycle or cyano; and n is 0 when X is said direct bond, or n is 1 when X is said alkylene or alkenylene. The compounds are effective in treating pain, and have effect in the peripheral nervous system, with comparably less or no activity in the central nervous system.

This invention relates to novel derivatives of compounds with opiatereceptor agonist or antagonist activity, such as analgesic or relatedpharmacological activity. In particular, the invention relates toderivatives of morphine-like opioid compounds in which an amidine groupof a particular structure is linked to the tertiary nitrogen atom of themorphine-like opioid.

BACKGROUND OF THE INVENTION

A range of therapeutic compounds are currently used in the treatment ofconditions such as allergies, diarrhoea, migraine and other painconditions, and in the treatment of congestive heart failure. Thesecompounds include compounds with analgesic or related activities, suchas anti-tussives, anti-depressants, local anaesthetics,anti-hypertensives, anti-asthmatics, anti-histamines, andanti-serotonins.

Many of the therapeutic compounds of the types enumerated above haveundesirable side-effects, such as the respiratory depression caused byopiates. In particular, many drugs which are useful for their action onthe peripheral nervous system have undesirable effects in the centralnervous system.

Thus opiates are the most powerful analgesics known, but theirusefulness is greatly limited by their side-effects, including severerespiratory depression, and ability to induce addiction and physicaldependence.

Despite intensive efforts to design analogues of morphine and relatedopioids which retain the analgesic activity, but which do not have adeleterious effect on the central nervous system and the bowel, successhas been limited. We have attempted to modify the ability ofbiologically-active compounds to cross the blood-brain barrier byincorporating a highly polar group into the molecular structure. Thus wehave shown that derivatives of the 2N atom of mianserin comprising aguanidino group show H₁ and 5-hydroxytryptamine activity, but show nodetectable activity in the central nervous system. In contrast, acompound in which the 2N atom of mianserin was substituted with a ureagroup still showed pronounced central nervous system activity (Jacksonet al; Clin. Ex. Pharmacol. Physiol., 1992 19 17-23 and our U.S. Pat.No. 5,049,637).

In our International patent application No. PCT/AU99/00062 (WO99/38869),we showed that compounds obtained by linking a highly charged group tothe tertiary nitrogen atom of a morphine-like opioid via a spacer groupnot only have reduced central side-effects, but retain activity atdesired peripheral receptors. We believe that this is a result of thedecreased lipophilicity of the compounds, and their resulting decreasedability to penetrate the blood-brain barrier. In particular, thosecompounds which show activities at opioid receptors retained broadanalgesic activity, contrary to the previously accepted state of theart, which teaches that the analgesic effects of morphine-like opioidsare mediated from the CNS. The selectivity of these compounds forperipheral opioid receptors not only makes them useful for the treatmentof pain without sedative or addictive effects, but also may make themuseful for treatment of AIDS and related immune deficiency diseases.

We have now surprisingly found that a particular range of compounds of anew structure have remarkably high analgesic activity, accompanied byreduced toxicity. These compounds also have the desired decreasedability to penetrate the blood-brain barrier.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides a compound of formula I

in which

YN is a morphine-like opioid radical;

X is—a direct bond,

-   -   an optionally substituted, branched, straight-chained or cyclic        alkylene having from 1 to 6 carbon atoms, optionally containing        one or two heteroatoms in the alkyl chain, or    -   an optionally substituted, branched or straight-chained        alkenylene having from 4 to 10 carbon atoms;

R and R′ are independently hydrogen, alkyl, substituted alkyl, alkene,substituted alkene, alkyne, substituted alkyne, aryl, substituted aryl,heterocycle, substituted heterocycle or cyano; and

n is 0 when X is said direct bond, or n is 1 when X is said alkylene oralkenylene;

or a pharmaceutically acceptable salt, hydrate, solvate,pharmaceutically acceptable derivative, pro-drug, tautomer and/or isomerthereof.

Preferably R is H, alkyl, phenyl, substituted phenyl, heterocycle orsubstituted heterocycle.

Preferably R′ is H, alkyl, substituted alkyl, phenyl, substitutedphenyl, heterocycle or substituted heterocycle.

It is preferred that at least one of R and R′ is not H. It is morepreferred that R′ is not H.

Preferably, at each instance, the heterocycle or substituted heterocycleis heteroaromatic or substituted heteroaromatic, respectively.

Preferably the substituent on the aryl or heteroaryl group is a C₁₋₆alkyl group such as methyl or ethyl, haloalkyl (including di- andtri-haloalkyls, such as trifluromethyl), hydroxy, amino, alkoxy,haloalkoxy, cyano, nitro, alkylthio, thiol, a salt or ester of aphosphorous-containing acid (such as phosphate or phosphite) or halo.

Where the alkyl, alkenyl or alkynyl groups referred to above aresubstituted, the preferred substituents are aryl, substituted aryl,heteroaromatic, substituted heteroaromatic, haloalkyl (including di- andtri-haloalkyls, such as trifluromethyl), hydroxy, amino, alkoxy,haloalkoxy, nitro, alkylthio, thiol, cyano or halo. Most preferably, inthe case of R′ being aryl or alkyl substituted with aryl, the preferredsubstituents on the aryl group (when aryl is substituted) are one ormore selected from alkyl, halo, alkoxy, hydroxy, nitro, cyano, a salt orester of a phosphorous-containing acid (such as phosphate or phosphite)and alkyl thio.

According to one embodiment, X is said alkylene and n is 1.

Preferably, the radical YN— is a radical of Formula II or Formula III:

wherein:R^(a) is H, C₁₋₄ alkyl, C₁₋₄ alkanoyl, C₁₋₄carboxyalkyl, or anO-protecting group;R^(b) is H, OH, protected hydroxy,C₁₋₄alkanoyloxy or C₁₋₄alkoxy; or, when C6 does not have a double bondto C7, and does not have an endoetheno or endoethano bridge to C14,R^(b) may be ═O or ═CH₂;R^(c) is H, OH or protected hydroxy;R^(d) is H or C₁₋₄ alkyl;R^(e) is H, CN, C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl, C₂₋₈ alkenyl,

in which R^(f) is H, alkyl, aryl, or alkaryl, and R^(g) is C₁₋₈ alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, each of these three groups being optionallysubstituted by aryl, or R^(g) is substituted aryl (the substituent(s) onthe aryl group being chosen from halo, alkyl, C₁₋₄alkoxy, haloalkyl),tetrahydrofuranyl, C₁₋₄ alkoxy;wherein the oxygen between C4 and C5 may or may not be present, asrepresented by the broken lines; wherein the brackets around the groupbetween C6 and C14 represents that the group may or may not be present,and when present the group may be an endoetheno or an endoethano bridge,as represented by the broken line; and wherein the dashed line betweenC6, C7, C8 and C14 represents that there is or are either zero, one ortwo double bonds, with the one double bond being either between C6 andC7, or C7 and C8, and the two double bonds being between C6 and C7, andC8 and C14;

whereinR^(h) is H or C₁₋₄ alkyl;R^(i) is H, OH, C₁₋₄ alkanoyl or C₁₋₄alkyl;R^(j) is H, OH, C₁₋₄ alkoxy, C₁₋₄ alkanoyl, C₁₋₄ alkanoyloxy; C₁₋₄carboxyalkyloxy or protected hydroxy; andR^(k) is H, OH, or protected hydroxy;and wherein the two dashed lines represent that the two bonds may beboth present or both absent.

In one embodiment of the invention, the radical YN— is a radical offormula II.

Preferably, the radical YN— is a radical of a compound selected from thegroup consisting of morphine, codeine, heroin, ethylmorphine,O-carboxymethylmorphine, O-acetylmorphine, hydrocodone, hydromorphone,oxymorphone, oxycodone, dihydrocodeine, thebaine, metopon, etorphine,acetorphine, ketobemidone, ethoheptazine, diprenorphine (M5050),buprenorphine, phenomorphan, levorphanol, pentazocine, eptazocine,metazocine, dihydroetorphine and dihydroacetorphine.

Preferably the radical YN— is a radical of morphine, codeine,buprenorphine or diprenorphine.

Particularly preferred compounds are as follows:

Z=alkyl, halo, alkoxy, hydroxy, cyano, nitro, alkyl thio.

In a second aspect, the invention provides a process for the preparationof a compound of formula I defined above which includes the step ofreacting a precursor for the radical YN— or YN—X—NH— with a precursorfor the radical

in which YN—, X, R, R′, R″ and n are as defined in formula I.

The reaction preferably includes the step of reacting YN—H or YN—X—NH₂with a compound of formula

in which R and R′ are as defined for the compound of formula I, and R″is alkyl, substituted alkyl, aryl or substituted aryl, to form acompound of Formula I.

According to a third aspect, the invention provides a pharmaceutical orveterinary composition comprising a compound according to formula I,together with a pharmaceutically or veterinarily acceptable carrier.

According to a fourth aspect, the invention provides a method oftreatment and/or prophylaxis of a condition or symptom that isinhibited, reduced or alleviated by opioid receptor activation,comprising administering a therapeutically effective amount of thecompound of formula I to a subject in need thereof. Preferably, themethod involves the treatment and/or prophylaxis of pain in theperipheral nervous system with comparably less or no activity on thecentral nervous system.

According to a fifth aspect, the invention provides a method of inducinganalgesia, comprising the step of administering an effective amount of acompound of formula I to a subject in need of such treatment.

According to a sixth aspect, the invention provides the use of acompound of formula I in the manufacture of a medicament for thetreatment and/or prophylaxis of a condition or symptom that isinhibited, reduced or alleviated by opioid receptor activation. Again,the condition or symptom is preferably pain.

The present invention also provides a compound of formula I for use inthe treatment and/or prophylaxis of a condition or symptom that isinhibited, reduced or alleviated by opioid receptor activation, such aspain.

The present invention further provides use of a compound for formula Ias an analgesic.

The present invention further provides a method of reducing the centralnervous system activity of a morphine-like opioid, comprising the stepof linking the nitrogen atom of the morphine-like opioid to the radical

in which X, R, R′ and n are as defined above.

DETAILED DESCRIPTION OF THE INVENTION

A number of terms of the art are used in this specification and theclaims, and they are described below for complete understanding of thescope of the invention.

The word “comprising” means “including but not limited to”, and the word“comprises” has a corresponding meaning.

The term “aryl” refers to single, polynuclear, conjugated and fusedresidues of aromatic hydrocarbons preferably having 6 to 20 carbonatoms, such as phenyl, biphenyl, terphenyl, quaterphenyl, phenoxyphenyl,naphthyl, anthryl and the like.

The term “alkyl” refers to a straight chain, branched, mono- orpoly-cyclic saturated hydrocarbon chain, preferably having from 1 to 10carbon atoms, most preferably 1 to 6 carbon atoms such as methyl, ethyl,n-propyl, isopropyl, n-butyl, secondary butyl, tert-butyl, n-hexyl,n-heptyl, n-octyl, n-decyl, n-dodecyl, 2-ethyldodecyl, tetradecyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unlessotherwise indicated. In some instances, the alkyl groups are said to beC₁₋₄ alkyl groups. When this term is used either alone or in a compoundword such as “optionally substituted C₁₋₄ alkoxy”, this term refers tostraight chained, branched or cyclic hydrocarbon groups having from 1 to4 carbon atoms. Illustrative of such alkyl groups are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyland tert-butyl.

The term “alkenyl” refers to a straight chain branched, mono- orpoly-cyclic unsaturated hydrocarbon chain, preferably having from 2 to10 carbon atoms, most preferably 2 to 6 carbon atoms such as vinyl,1-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl, 1-pentenyl,1-hexenyl, 3-hexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, 1-nonenyl,2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl,1-4,pentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl and the like, unless otherwiseindicated.

The term “alkynyl” refers to a straight chain, branched, mono- orpoly-cyclic unsaturated hydrocarbon chain, preferably having from 2 to10 carbon atoms, most preferably 2 to 6 carbon atoms such as ethynyl,1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl,10-undecynyl, 4-ethyl-1-octyn-3-yl, 7-dodecynyl, 9-dodecynyl,10-dodecynyl, 3-methyl-1-dodecyn-3-yl, 2-tridecynyl, 11-tridecynyl,3-tetradecynyl, 7-hexadecynyl, 3-octadecynyl and the like, unlessotherwise indicated.

The terms “alkylene”, “alkenylene” and “alkynylene” are the divalentradical equivalents of the terms “alkyl”, “alkenyl” and “alkynyl”,respectively. The two bonds connecting the alkylene, alkenylene oralkynylene to the adjacent groups may come from the same carbon atom ordifferent carbon atoms in the divalent radical.

The term “heterocycle” refers to a cyclic alkyl, alkenyl or alkynylgroup of from 1 to 12 carbon atoms containing at least one heteroatomselected from oxygen, nitrogen and sulphur. Examples include unsaturated3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogenatoms, such as, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl;

saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidino orpiperazinyl;

unsaturated condensed heterocyclic groups containing 1 to 5 nitrogenatoms, such as, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl ortetrazolopyridazinyl;

unsaturated 3 to 6-membered heteromonocyclic group containing an oxygenatom, such as, pyranyl or furyl;

unsaturated 3 to 6-membered hetermonocyclic group containing 1 to 2sulphur atoms, such as, thienyl;

unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, such as, oxazolyl, isoxazolyl oroxadiazolyl;

saturated 3 to 6-membered heteromonocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl;

unsaturated condensed heterocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl;

unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolyl orthiadiazolyl;

saturated 3 to 6-membered heteromonocyclic group containing 1 to 2sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolidinyl; and

unsaturated condensed heterocyclic group containing 1 to 2 sulphur atomsand 1 to 3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolylheteroatom selected from oxygen, nitrogen and sulphur.

The term “heteraromatic” refers to any of the unsaturated heterocycliccompounds defined above which are also aromatic.

Suitable substituents include halo, alkyl, alkene, alkyne, aryl,heterocyclic, haloalkyl, haloalkene, haloalkyne, acyl, acyloxy, hydroxy,amino, substituted amino groups such as NHacyl, alkylamino, cyano,nitro, thio, alkylthio, carboxy, sulphonic acid, sulphoxides,sulphonamides, quaternary ammonium groups and alkoxy groups such asmethoxy, alkenyloxy, alkynyloxy haloalkoxy, haloalkenyloxy,haloalkynyloxy and are preferably F, Cl, hydroxy, C₁₋₆alkoxy,C₁₋₆alkylamino or carboxy.

Halo will be understood to mean Cl, F, Br or I.

The term “optionally substituted” refers to a group may or may not befurther substituted with one or more groups selected from alkyl,alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl,haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy,haloalkenyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl,nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino,dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino,benzylamino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl,acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy,heterocyclyl, heterocycloxy, heterocyclamino, haloheterocyclyl,alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy, mercapto,alkylthio, benzylthio, acylthio, phosphorus-containing groups and thelike. In some instances in this specification, where substituents may bepresent, preferred substituents have been mentioned.

Protecting groups may in general be chosen from any of the groupsdescribed in the literature or known to the skilled chemist appropriatefor the protection of the group in question, and may be introduced byconventional methods.

Protecting groups may be removed by any convenient method as describedin the literature or known to the skilled chemist as appropriate for theremoval of the protecting group in question, such methods being chosenso as to effect removal of the protecting group with minimum disturbanceof groups elsewhere in the molecule.

Examples of hydroxyl protecting groups include lower alkyl groups (eg.t-butyl), lower alkenyl groups (eg. allyl); lower alkanoyl groups (eg.acetyl); lower alkoxycarbonyl groups (eg. t-butoxycarbonyl); loweralkenyloxycarbonyl groups (eg. allyloxycarbonyl); aryl loweralkoxycarbonyl groups (eg. benzoyloxycarbonyl,p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl); tri(lower alkyl)silyl (eg. trimethylsilyl,t-butyldimethylsilyl) and aryl lower alkyl (eg. benzyl) groups. Anacetyl group is preferred.

Methods appropriate for removal of hydroxy protecting groups include,for example, acid-, base-, metal- or enzymically-catalysed hydrolysis,for groups such as p-nitrobenzyloxycarbonyl, hydrogenation and forgroups such as o-nitrobenzyloxycarbonyl, photolytically.

The term “morphine-like opioid” is used herein in its broadest sense andrefers to any compounds, natural or synthetic, having a morphine-likeaction. The term encompasses morphine and its natural and semisyntheticderivatives, together with other chemical classes of drugs withpharmacological actions similar to those of morphine. Compounds in thesegroups have agonistic (including competitive or partial agonistic)activity on at least one of the opiate receptors. Hence, these compoundsvariably have the capacity to produce analgesia, respiratory depression,gastrointestinal spasm and/or morphine-like physical dependence. Groupsof compounds in this class include morphinans (in which the C7 to C8double bond is a single bond, and optionally the ether oxygen betweenpositions 4 and 5 is removed), the morphinones and dihydromorphinones(in which the OH at C6 is replaced with ═O, and optionally the C7 to C8double bond is a single bond, and also optionally the ether oxygenbetween C4 and C5 is not present), the Diels-Alder adducts of thebaine(in which there is an endoetheno bridge between C6 and C14, or anendoethano bridge between C6 and C14, and optionally a C7 substitution),benzomorphans (in which the cycloalkene ring and the tetrahydrofuranrings are absent) and phenylpiperidines. Such compounds are well knownin the art; see for example “The Pharmacological Basis of Therapeutics”(ed. A. G. Gilman et al; 7^(th) edition, 1985, chapter 22). It will beclearly understood that all of the compounds set out in Table 1 ofPCT/AU99/00062 are suitable for use in the invention.

The radical form of the morphine-like opioid is constituted by themorphine-like opioid with the atom or group on the nitrogen of themorphine-like opioid removed.

Structurally, the morphine-like opioid radicals include the radicals offormulae II and III defined above.

The radicals encompassed by the structure of Figure II may be dividedinto a number of groups:

-   (a) the morphine derivatives in which there is a single double bond    between C7 and C8 (or C6 and C8, as in the case of pseudocodeine),    and there is no bridging group between C6 and C14;-   (b) the morphinan derivatives in which there are no double bonds    between any of C6, C7, C8 and C14, and no bridging group between C6    and C14, (including one subclass in which R^(b) is H, and another in    which R^(b) is ═CH₂);-   (c) the morphinone derivatives, in which R^(b) is ═O, and there is    no bridging group between C6 and C14 (including the subclass of    dihydromorphinones, in which there are also no double bonds between    any of C6, C7, C8 and C14); and-   (d) the thebaine derivatives (Diels-Alder adducts of thebaine), in    which there is an endoetheno or an endoethano bridge between C6 and    C14 (including the particularly important subclass where R^(e) is    (figure)).

The radicals encompassed by the structure of Figure III may be dividedinto a number of groups including:

-   (e) the benzomorphan derivatives, in which the bonds represented by    the broken lines are present; and-   (f) the phenylpiperidines, in which the bonds represented by the    broken lines are not present (including the significant subclass in    which R^(i) is C₁₋₄ alkanoyl).

For the synthesis of the compounds of formula I, the precursors forradical components are utilised. A precursor for a radical is either:

-   -   a compound containing the radical coupled to a functional group        that is removed during reaction to couple the radical to another        radical; or    -   a compound from which the radical is formed by chemical        rearrangement during the reaction, with removal of an atom or        group from the compound.

For the first type of precursor, suitable functional groups depend onthe reaction being conducted, and may for instance be hydrogen, anamine, halogen, alcohol, and so forth.

It will be appreciated by those skilled in the art that the compounds offormula I may be modified to provide pharmaceutically acceptablederivatives thereof at any of the functional groups in the compounds offormula I. Of particular interest as such derivatives are compoundsmodified at the carboxyl function, hydroxyl functions or at theguanidino or amino groups. Thus compounds of interest include C₁₋₆alkylesters, such as methyl, ethyl, propyl or isopropyl esters, aryl esters,such as phenyl, benzoyl esters, and C₁₋₆acetyl esters of the compoundsof formula I. Consequently, the term “pharmaceutically acceptablederivative” means any pharmaceutically acceptable salt, ester or salt ofsuch ester of a compound of formula I or any other compound which, uponadministration to the recipient, is capable of providing (directly orindirectly) a compound of formula I or a biologically active metaboliteor residue thereof.

Pharmaceutically acceptable salts of the compounds of formula I includethose derived from pharmaceutically acceptable cations, inorganic andorganic acids and bases. Examples of pharmaceutically acceptable saltsinclude salts of pharmaceutically acceptable cations such as sodium,potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acidaddition salts of pharmaceutically acceptable inorganic acids such ashydrochloric, orthophosphoric, sulphuric, phosphoric, nitric, carbonic,boric, sulfamic and hydrobromic acids; or salts of pharmaceuticallyacceptable organic acids such as acetic, propionic, butyric, tartaric,maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic,benzoic, succinic, oxalic, phenylacetic, methanesulphonic,trihalomethanesulphonic, toluenesulphonic, benzenesulphonic, salicylic,sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic,lauric, pantothenic, tannic, ascorbic and valeric acids. Some of theacids mentioned above such as oxalic acid, while not in themselvespharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining compounds of the invention andtheir pharmaceutically acceptable acid addition salts.

The term “pro-drug” is used herein in its broadest sense to includethose compounds which are converted in vivo to compounds of Formula I.

The term “tautomer” is used herein in its broadest sense to includecompounds of Formula I which are capable of existing in a state ofequilibrium between two isomeric forms. Such compounds may differ in thebond connecting two atoms or groups and the position of these atoms orgroups in the compound.

The term “isomer” is used herein in its broadest sense and includesstructural, geometric and stereo isomers. As the compound of Formula Ihave one or more chiral centres, it is capable of existing inenantiomeric forms.

Some compounds of the invention are optically active, and it will beclearly understood that both racemic mixtures and isolated stereoisomersare within the scope of the invention. A method of separatingenantiomers of mianserin-like compounds with a guanidino-typesubstituent is disclosed in our International patent application No.PCT/AU98/00807 (WO99/16769), and could be used with the compounds of theinvention. Other methods of resolution for amino compounds aresummarised in Chapter 7, Separation of Stereoisomers. Resolution.Racemisation, pages 297-421 of E. L. Eliel, S. H. Wilen and L. N.Mander, Stereochemisty of Organic Compounds, Wiley-Interscience, NewYork, 1994.

The compositions of the present invention comprise at least one compoundof Formula I together with one or more pharmaceutically acceptablecarriers and optionally other therapeutic agents. Each carrier, diluent,adjuvant and/or excipient must be pharmaceutically “acceptable” in thesense of being compatible with the other ingredients of the compositionand not injurious to the subject. Compositions include those suitablefor oral, rectal, nasal, topical (including buccal and sublingual),vaginal or parenteral (including subcutaneous, intramuscular,intravenous and intradermal) administration. The compositions mayconveniently be presented in unit dosage form and may be prepared bymethods well known in the art of pharmacy. Such methods include the stepof bringing into association the active ingredient with the carrierwhich constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers, diluents,adjuvants and/or excipients or finely divided solid carriers or both,and then if necessary shaping the product.

The compounds of the present invention may be used to treat a conditionor symptom that is inhibited, reduced or alleviated by opioid receptoractivation. This refers to conditions or symptoms that are associatedwith one or more of the nervous system, vascular system,gastrointestinal system, pulmonary system and heart. Examples of suchconditions are pain, pulmonary edema and diarrhoea.

It will be understood that the brain and spinal cord are CNS organswhich lie principally inside (central to) the blood brain barrier.Accordingly, an agent with “reduced or no CNS activity” will actprimarily with cells or tissues of the body which lie outside(peripheral to) the blood brain barrier. The specificity for “reduced orno CNS activity” may be a result of the inhibition of the passage of theagent from the circulation across the blood brain barrier into the CNS.

The term “subject” as used herein refers to any animal having a diseaseor condition which requires treatment with a pharmaceutically-activeagent. The subject may be a mammal, preferably a human, or may be adomestic or companion animal. While it is particularly contemplated thatthe compounds of the invention are suitable for use in medical treatmentof humans, it is also applicable to veterinary treatment, includingtreatment of companion animals such as dogs and cats, and domesticanimals such as horses, ponies, donkeys, mules, llama, alpaca, pigs,cattle and sheep, or zoo animals such as primates, felids, canids,bovids, and ungulates.

Suitable mammals include members of the Orders Primates, Rodentia,Lagomorpha, Cetacea, Carnivora, Perissodactyla and Artiodactyla. Membersof the Orders Perissodactyla and Artiodactyla are particularly preferredbecause of their similar biology and economic importance.

For example, Artiodactyla comprises approximately 150 living speciesdistributed through nine families: pigs (Suidae), peccaries(Tayassuidae), hippopotamuses (Hippopotamidae), camels (Camelidae),chevrotains (Tragulidae), giraffes and okapi (Giraffidae), deer(Cervidae), pronghorn (Antilocapridae), and cattle, sheep, goats andantelope (Bovidae). Many of these animals are used as feed animals invarious countries. More importantly, many of the economically importantanimals such as goats, sheep, cattle and pigs have very similar biologyand share high degrees of genomic homology.

The Order Perissodactyla comprises horses and donkeys, which are botheconomically important and closely related. Indeed, it is well knownthat horses and donkeys interbreed.

As used herein, the term “therapeutically effective amount” is meant anamount of a compound of the present invention effective to yield adesired therapeutic response, for example, to induce analgesia.

The specific “therapeutically effective amount” will, obviously, varywith such factors as the particular condition being treated, thephysical condition of the subject, the type of subject being treated,the duration of the treatment, the nature of concurrent therapy (ifany), and the specific formulations employed and the structure of thecompound or its derivatives.

The compounds of the present invention may additionally be combined withother medicaments to provide an operative combination. It is intended toinclude any chemically compatible combination of pharmaceutically-activeagents, as long as the combination does not eliminate the activity ofthe compound of formula I. It will be appreciated that the compound ofthe invention and the other medicament may be administered separately,sequentially or simultaneously.

Methods and pharmaceutical carriers for preparation of pharmaceuticalcompositions are well known in the art, as set out in textbooks such asRemington's Pharmaceutical Sciences, 20th Edition, Williams & Wilkins,Pennsylvania, USA.

As used herein, a “pharmaceutical carrier” is a pharmaceuticallyacceptable solvent, suspending agent or vehicle for delivering thecompound of formula I to the subject. The carrier may be liquid or solidand is selected with the planned manner of administration in mind. Eachcarrier must be pharmaceutically “acceptable” in the sense of beingcompatible with other ingredients of the composition and non injuriousto the subject.

The compound of formula I may be administered orally, topically, orparenterally in dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles.The term parenteral as used herein includes subcutaneous injections,aerosol for administration to lungs or nasal cavity, intravenous,intramuscular, intrathecal, intracranial, injection or infusiontechniques.

The present invention also provides suitable topical, oral, andparenteral pharmaceutical formulations for use in the novel methods oftreatment of the present invention. The compounds of the presentinvention may be administered orally as tablets, aqueous or oilysuspensions, lozenges, troches, powders, granules, emulsions, capsules,syrups or elixirs. The composition for oral use may contain one or moreagents selected from the group of sweetening agents, flavouring agents,colouring agents and preserving agents in order to producepharmaceutically elegant and palatable preparations. Suitable sweetenersinclude sucrose, lactose, glucose, aspartame or saccharin. Suitabledisintegrating agents include corn starch, methylcellulose,polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.Suitable flavouring agents include peppermint oil, oil of wintergreen,cherry, orange or raspberry flavouring. Suitable preservatives includesodium benzoate, vitamin E, alphatocopherol, ascorbic acid, methylparaben, propyl paraben or sodium bisulphite. Suitable lubricantsinclude magnesium stearate, stearic acid, sodium oleate, sodium chlorideor talc. Suitable time delay agents include glyceryl monostearate orglyceryl distearate. The tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets.

These excipients may be, for example, (1) inert diluents, such ascalcium carbonate, lactose, calcium phosphate or sodium phosphate; (2)granulating and disintegrating agents, such as corn starch or alginicacid; (3) binding agents, such as starch, gelatin or acacia; and (4)lubricating agents, such as magnesium stearate, stearic acid or talc.These tablets may be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate maybe employed. Coating may also be performed using techniques described inthe U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

The compound of formula I as well as the pharmaceutically-active agentuseful in the method of the invention can be administered, for in vivoapplication, parenterally by injection or by gradual perfusion over timeindependently or together. Administration may be intravenously,intraarterial, intraperitoneally, intramuscularly, subcutaneously,intracavity, transdermally or infusion by, for example, osmotic pump.For in vitro studies the agents may be added or dissolved in anappropriate biologically acceptable buffer and added to a cell ortissue.

Preparations for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions, and emulsions. Examples ofnon-aqueous solvents are propylene glycol, polyethylene glycol,vegetable oils such as olive oil, and injectable organic esters such asethyl oleate. Aqueous carriers include water, alcoholic/aqueoussolutions, emulsions or suspensions, including saline and bufferedmedia. Parenteral vehicles include sodium chloride solution, Ringer'sdextrose, dextrose and sodium chloride, lactated Ringer's intravenousvehicles include fluid and nutrient replenishers, electrolytereplenishers (such as those based on Ringer's dextrose), and the like.Preservatives and other additives may also be present such as, forexample, anti-microbials, anti-oxidants, chelating agents, growthfactors and inert gases and the like.

Generally, the terms “treating”, “treatment” and the like are usedherein to mean affecting a subject or tissue to obtain a desiredpharmacologic and/or physiologic effect. The effect may be thealteration of the perception of nociceptive stimuli. The effect may beprophylactic in terms of completely or partially preventing a sensation,condition, symptom or disease, and/or may be therapeutic in terms of apartial or complete removal of a sensation, condition or symptom, orcure of a disease. In the context of analgesia, the term “treating”covers the treatment of, or prevention of, the sensation of pain.“Treating” as used herein in any other context covers any treatment of,or prevention of, condition, symptom or disease in a vertebrate, amammal, particularly a human, and includes: (a) preventing thecondition, symptom or disease from occurring in a subject that may bepredisposed to the condition, symptom or disease, but has not yet beendiagnosed as having it; (b) inhibiting the disease, i.e., arresting itsdevelopment; or (c) relieving or ameliorating the effects of thedisease, i.e., cause regression of the effects of the disease.

The invention includes various pharmaceutical compositions useful forameliorating a sensation (such as pain) or disease. The pharmaceuticalcompositions according to one embodiment of the invention are preparedby bringing a compound of formula I, analogues, derivatives or saltsthereof, or combinations of compound of formula I and one or morepharmaceutically-active agents into a form suitable for administrationto a subject using carriers, excipients and additives or auxiliaries.Frequently used carriers or auxiliaries include magnesium carbonate,titanium dioxide, lactose, mannitol and other sugars, talc, milkprotein, gelatin, starch, vitamins, cellulose and its derivatives,animal and vegetable oils, polyethylene glycols and solvents, such assterile water, alcohols, glycerol and polyhydric alcohols. Intravenousvehicles include fluid and nutrient replenishers. Preservatives includeantimicrobial, anti-oxidants, chelating agents and inert gases. Otherpharmaceutically acceptable carriers include aqueous solutions,non-toxic excipients, including salts, preservatives, buffers and thelike, as described, for instance, in Remington's PharmaceuticalSciences, 20th ed. Williams and Wilkins (2000) and The British NationalFormulary 43rd ed. (British Medical Association and Royal PharmaceuticalSociety of Great Britain, 2002; http://bnf.rhn.net), the contents ofwhich are hereby incorporated by reference. The pH and exactconcentration of the various components of the pharmaceuticalcomposition are adjusted according to routine skills in the art. SeeGoodman and Gilman's The Pharmacological Basis for Therapeutics (7thed., 1985).

The pharmaceutical compositions are preferably prepared and administeredin dose units. Solid dose units may be tablets, capsules andsuppositories. For treatment of a subject, depending on activity of thecompound, manner of administration, nature and severity of the disorder,age and body weight of the subject, different daily doses can be used.Under certain circumstances, however, higher or lower daily doses may beappropriate. The administration of the daily dose can be carried outboth by single administration in the form of an individual dose unit orelse several smaller dose units and also by multiple administration ofsubdivided doses at specific intervals.

The pharmaceutical compositions according to the invention may beadministered locally or systemically in a therapeutically effectivedose. Amounts effective for this use will, of course, depend on theseverity of the disease and the weight and general state of the subject.Typically, dosages used in vitro may provide useful guidance in theamounts useful for in situ administration of the pharmaceuticalcomposition, and animal models may be used to determine effectivedosages for treatment of the cytotoxic side effects. Variousconsiderations are described, e.g., in Langer, Science, 249: 1527,(1990). Formulations for oral use may be in the form of hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin.They may also be in the form of soft gelatin capsules wherein the activeingredient is mixed with water or an oil medium, such as peanut oil,liquid paraffin or olive oil.

Aqueous suspensions normally contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspension. Suchexcipients may be (1) suspending agent such as sodium carboxymethylcellulose, methyl cellulose, hydroxypropylmethylcellulose, sodiumalginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2)dispersing or wetting agents which may be (a) naturally occurringphosphatide such as lecithin; (b) a condensation product of an alkyleneoxide with a fatty acid, for example, polyoxyethylene stearate; (c) acondensation product of ethylene oxide with a long chain aliphaticalcohol, for example, heptadecaethylenoxycetanol; (d) a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand hexitol such as polyoxyethylene sorbitol monooleate, or (e) acondensation product of ethylene oxide with a partial ester derived fromfatty acids and hexitol anhydrides, for example polyoxyethylene sorbitanmonooleate.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to known methods using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

Compounds of formula I may also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles, and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, such as cholesterol, stearylamine, orphosphatidylcholines.

The compounds of formula I may also be presented for use in the form ofveterinary compositions, which may be prepared, for example, by methodsthat are conventional in the art. Examples of such veterinarycompositions include those adapted for:

(a) oral administration, external application, for example drenches(e.g. aqueous or non-aqueous solutions or suspensions); tablets orboluses; powders, granules or pellets for admixture with feed stuffs;pastes for application to the tongue;

(b) parenteral administration for example by subcutaneous, intramuscularor intravenous injection, e.g. as a sterile solution or suspension; or(when appropriate) by intramammary injection where a suspension orsolution is introduced in the udder via the teat;

(c) topical applications, e.g. as a cream, ointment or spray applied tothe skin; or

(d) intravaginally, e.g. as a pessary, cream or foam.

Dosage levels of the compound of formula I of the present invention areof the order of about 0.5 mg to about 20 mg per kilogram body weight,with a preferred dosage range between about 0.5 mg to about 10 mg perkilogram body weight per day (from about 5 mg to about 3 g per patientper day, but in the case of palliative care patients about 5 g to about10 g per patient per day). The amount of active ingredient that may becombined with the carrier materials to produce a single dosage will varydepending upon the host treated and the particular mode ofadministration. For example, a formulation intended for oraladministration to humans may contain about 5 mg to 1 g of an activecompound with an appropriate and convenient amount of carrier materialwhich may vary from about 5 to 95 percent of the total composition.Dosage unit forms will generally contain between from about 5 mg to 500mg of active ingredient.

Optionally the compounds of the invention are administered in a divideddose schedule, such that there are at least two administrations in totalin the schedule. Administrations are given preferably at least every twohours for up to four hours or longer; for example the compound may beadministered every hour or every half hour. In one preferred embodiment,the divided-dose regimen comprises a second administration of thecompound of the invention after an interval from the firstadministration sufficiently long that the level of active compound inthe blood has decreased to approximately from 5-30% of the maximumplasma level reached after the first administration, so as to maintainan effective content of active agent in the blood. Optionally one ormore subsequent administrations may be given at a corresponding intervalfrom each preceding administration, preferably when the plasma level hasdecreased to approximately from 10-50% of the immediately-precedingmaximum.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

EXAMPLES

The invention will now be described in detail by way of reference onlyto the following non-limiting examples and drawings.

Example 1 Preparation of Precursors YN—X—NH₂ where X is Straight ChainAlkylene

Methods of synthesis of amine precursors of compounds containing astraight-chained alkyl group as the spacer group “X” are disclosed inPCT/AU99/00062, the full disclosure of which is incorporated into thisdocument by reference. This method yields the precursor compoundYN(CH)_(n)NH₂. One example is provided below.

Example 1a Preparation of3,6-bis(t-butyldimethyl-siloxy)-7,8-didehydro-4,5-epoxy-17-(2-cyanoethyl)morphinan

-   -   Ref: J. A. Bell and C. Kenworthy, Synthesis, 650-652, 1971.

3,6-Bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxymorphinan (0.26 g,0.52 mmol) was dissolved in absolute ethanol (3 mL) and acrylonitrile(0.07 ml, 1.0 mmol) was added dropwise at room temperature. The reactionmixture was stirred at room temperature overnight, and the solvent wasevaporated under reduced pressure to give a white solid (0.26 g, 90%yield).

Example 1b Preparation of3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-(aminopropyl)morphinan

A solution of3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-(2-cyanoethyl)morphinan(200 mg, 0.36 mmol) in dry ethyl ether (5 ml) was added dropwise to asuspension of lithium aluminum hydride (0.13 g, 3.6 mmol) in dry ethylether (5 ml). After stirring for 3 h at room temperature the reactionmixture was added wet ether followed by 10% sodium hydroxide (1.5 ml).The solution was filtered, and the white precipitate was washed withether. The ether layer was evaporated under reduced pressure to give theamine as a clear liquid (yield=0.2 g, 99%).

Example 2 Preparation of Precursors YN—X—NH₂ where X is Branched ChainAlkylene

Examples 1a and 1b are repeated using the following readily availablecompounds in place of acrylonitrile, to yield the corresponding amineprecursor YN—X—NH₂ in which X is the corresponding branched chain alkyl.

Example 3 Preparation of Precursors YN—X—NH₂ where X is Branched ChainAlkylene

As an alternative to Example 2, precursors YN—X—NH₂ are prepared byreaction of the demethylated opioid with α-aminoacids yielding an amide,which can be reduced to an amine containing a branch chain with onecarbon atom in the spacer. A wide variety of α-aminoacids arecommercially available.

As another alternative to Example 2, β-aminoacids (eg. 3-aminobutanoicacid) are used to produce compounds with a branched chain group withthree carbon atoms in the main chain.

Example 4 Preparation of Precursors YN—X—NH₂ where X is Alkenylene

The method disclosed in Albeck, A. et al, Tetrahedron, 2000, 56,1505-1516, is used to prepare the compound containing the protectedamino group at one end and hydroxy group at the other end illustrated inthe scheme set out above. This compound is then brominated (step 1)using the method and conditions specified in D. Poirier et al, Tet.Lett., Vol 35, 7, 1051, 1995. The brominated product is reacted with theopioid using the conditions and methods set out in one of the followingthree references:

-   1. NaOH/isopropanol—Limanov, V. E., Myazina, N. V. Zh, Prikl Khim.    1988, 61(10), 2365-8.-   2. KOH/triethyl amine—Mohri, K. Suzuki, K, Usui M, Isobe, K,    Tsuda, Y. Chemical & Pharmaceutical Bulletin 1995, 43 (1), 159-61.-   3. CsOH—Salvatore, R. Nagle, A. Schmidt, S. Jung, K. Organic    Letters, 1999, 1(12), 1893-96.

Thereafter, the amine is deprotected following the method and conditionsoutlined in Albeck et al, to yield YN—X—NH₂ in which X is an alkenylene.

Example 5 Preparation of Precursors YN—X—NH₂ where X is Ether-ContainingAlkylene

Standard chemical reactions can be used in the sequence outlined belowto prepare precursor YN—X—NH₂ in which X is an ether-containingalkylene. The individual reactions are conducted in standard conditionsfor the given types of reactions.

An alternative route for the synthesis of the precursor YN—X—NH₂ inwhich X is an ether-containing alkylene is outlined below. Again, eachindividual reaction is of a standard class of reaction.

Alternatively

Example 6 Preparation of Subject Amidines from YN—X—NH₂ or YN—H

Once the precursor YN—X—NH₂ has been synthesised by one of the methodsoutlined above (or below), the amidine is synthesised by reacting theamine YN—X—NH₂ with the appropriate imidate. The conditions for thisreaction are as set forth in Sandler, S. R., Karo, W. Imidates inOrganic Chemistry; Academic Press, New York, 1972, Chapter 8, Vol 3,pages 268-300. This is illustrated in the following reaction scheme withthe ethyl imidate:

Using this procedure, the following compounds are prepared from thegiven starting materials: Opioid Imidate Product Morphine

Morphine

Amidine

Morphine

Morphine

Morphine

Morphine

Morphine

Morphine

Z=alkyl, halo, alkoxy, hydroxy, cyano, nitro, alkyl thio.

Example 7 Synthesis of(5α,6α)-7,8-didehydro-4,5-epoxy-17-((N-phenylpropionamidino)-propyl)morphinan,3,6-diol (KRS-6-48)

Preparation of3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-((N-phenylpropionamidino)-propyl)morphinan

Ethyl N-phenylpropanimidate was prepared according to the proceduredisclosed in Sandler and Karo (1972)(see Example 6 for full reference).A solution of freshly prepared ethyl N-phenylpropanimidate (89 mg, 0.539mmol) in acetonitrile (1 ml) was added to a solution of 3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-(3-aminopropyl)morphinan(200 mg, 0.359 mmol) in acetonitrile (1 ml) and methanol (1 ml) and wasstirred overnight at room temperature under N₂. The reaction mixture wasevaporated to dryness and the crude residue was purified by columnchromatography on silica gel using methylene chloride/methanol/ammoniumhydroxide 9:1:0.1 to give the protected amidine as a white solid (0.148g, 60% yield).

Preparation of(5α,6α)-7,8-didehydro-4,5-epoxy-17-((N-phenylpropionamidino)-propyl)morphinan,3,6-diol (KRS-6-48)

3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-((N-phenylpropionamidino)-propyl)-morphinan(143 mg, 0.208 mmol) in methanol (10 ml) was added ammonium fluoride(0.08 g, 2.08 mmol) and the reaction mixture was stirred overnight atroom temperature under N₂. The reaction mixture was evaporated todryness and the crude was purified by column chromatography on silicagel using methylene chloride/methanol/ammonium hydroxide 9:2:0.2 to givethe amidine as a white solid (82 mg, 85% yield). M.P. 188-190° C. (HClsalt)

Example 8 Synthesis of(5α,6α)-7,8-didehydro-4,5-epoxy-17-(3-acetamidinopropyl)morphinan,3,6-diol (KRS-6-41)

Preparation of 3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-(3-acetamidinopropyl)morphinan

A solution of ethyl acetimidate hydrochloride (0.037 g, 0.295 mol) and3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-(3-aminopropyl)morphinan(150 mg, 0.269 mmol) in acetonitrile (1 ml) and methanol (1 ml) wasstirred at room temperature for 3 days. The reaction mixture wasevaporated to dryness and the crude residue was chromatographed onsilica gel using methylene chloride/methanol/ammonium hydroxide 9:2:0.2as the eluent to give the protected amidine. (0.139 g, 86% yield)

Preparation of(5α,6α)-7,8-didehydro-4,5-epoxy-17-(3-acetamidinopropyl)morphinan,3,6-diol (KRS-6-41)

The protected amidine was deprotected using ammonium fluoride inmethanol using the same procedure described in Example 7 to giveKRS-6-41 as a white solid (74 mg, 86% yield) M.P. 156-160° C.

Example 9 Synthesis of(5α,6α)-7,8-didehydro-4,5-epoxy-17-((N-phenylacetamidino)-propyl)morphinan,3,6-diol (KRS-6-51)

(5α,6α)-7,8-didehydro-4,5-epoxy-17-((N-phenylacetamidino)-propyl)morphinan,3,6-diol (KRS-6-51) was prepared following the procedure detailed inExample 7 using ethyl N-phenylacetimidate which was prepared accordingto Sandler and Karo (1972). M.P. 120° C.

Example 10 Synthesis of(5α,6α)-7,8-didehydro-4,5-epoxy-17-((N-(2-ethylphenyl)propionamidino)-propyl)morphinan,3,6-diol (KRS-6-71)

Preparation of3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-((N-(2-ethylphenyl)propionamidino)-propyl)morphinan

Ethyl N-(2-ethylphenyl)-propanimidate was prepared from 2-ethylanilineand triethylorthopropionate. A solution ofethyl-N-(2-ethylphenyl)-propanimidate (0.235 g, 0.0011 mol) inacetonitrile (1.5 ml) was added to a solution of 3,6-bis(t-butyldimethylsiloxy)-7,8-didehydro-4,5-epoxy-17-(3-aminopropyl)morphinan(0.425 g, 0.76 mmol) in acetonitrile (1 ml) and methanol (1 ml). Thereaction mixture was stirred for 2 days at room temperature under N₂ andevaporated to dryness. The crude was chromatographed on silica gel usingmethylene chloride/methanol/ammonium hydroxide in 9:2:0.2 ratio to givethe protected amidine as a thick liquid in 85% yield.

Preparation of(5α,6α)-7,8-didehydro-4,5-epoxy-17-((N-(2-ethylphenyl)propionamidino)-propyl)morphinan,3,6-diol (KRS-6-71)

The amidine was deprotected using ammonium fluoride according to theprocedure outlined in Example 7 above and purified by columnchromatography to give KRS-6-71 as a white solid in 87% yield. M.P.58-59° C.

Example 11 Synthesis of(5α,6α)-7,8-didehydro-4,5-epoxy-17-(N-(4-fluorophenyl)propionamidino)-propyl)morphinan,3,6-diol (KRS-6-98)

Ethyl-N-(4-fluorophenyl)-propionimidate was prepared from4-fluoroaniline and triethylorthopropionate. A solution ofethyl-N-(4-fluorophenyl)-propionimidate (0.114 g, 0.584 mmol) inacetonitrile was added to a solution of 3,6-bis(t-butylsiloxy)-7,8-didehydro-4,5-epoxy-17-N-(3-aminopropyl)morphinan(250 mg, 0.449 mmol) in acetonitrile (1 mL) and methanol (1 ml). Thereaction mixture was stirred at room temperature under N₂ and wasmonitored by TLC. After stirring for 2 days, the reaction mixture wasevaporated to dryness and the crude was chromatographed on silica gelusing methylene chloride/methanol/ammonium hydroxide in 9:1:0.1 ratio togive the t-butyldimethylsilyl protected amidine. This was deprotected asdescribed in Example 7 to give KRS-6-98 as a white solid in 43% yield.(M.P. 106° C.).

Example 12 Analgesic Activity of KRS-6-48

Testing on compound KRS-6-48 was carried out under contract by MDSServices—Taiwan Ltd. KRS-6-48 was evaluated for possible analgesicactivity in the phenylquinone-induced writhing model in mice (Siegmundet al, 1957). A serial 2-fold dosage variance was used in the test, from128 mg/kg to 1 mg/kg (8 doses in total). Groups of 3 male or female ICRmice weighing 22±2 g were employed. Variant doses (1, 2, 4, 8, 16, 32,64 and 128 mg/kg) of test substances were administered intraperitoneally(IP). A vehicle of 2% Tween 80 in 0.9% NaCl was used for theintraperitoneal injection. The control group received vehicle alone.Phenylquinone (PQ) at dose of 2 mg/kg was injected intraperitoneally 30minutes (IP) after test substance, and the number of writhes exhibitedduring the following 5-10 minute period was recorded. A reduction in thenumber of writhes by 50 percent or more (≧50%) relative to thevehicle-treated group indicated possible analgesic activity.

KRS-6-48

Very significant activity was found for KRS-6-48 at doses of 128, 64, 32and 16 mg/kg. These results are summarised in Table 1. KRS-6-48 did notexhibit Straub tail behaviour at any doses. The Straub test is anindicator of CNS activity. In contrast to this finding, in response tomorphine at 3 mg/kg, 2 of 3 test animals exhibited the Straub tailphenomenon. This indicates that KRS-6-48 is able to exert an analgesiceffect without a central effect on the central nervous system. At 128mg/kg (IP), 3 or 3 test animals exhibited twitch and muscle relaxation.TABLE 1 Analgesia in the Phenylquinone Writhing Model % In hi- No. ofWrithings bi- Treatment Route Dose N Individual Average tion Vehicle IP10 ml/kg 1 15 (2% Tween 2 13 80/0.9% NaCl) 3 10 13 — (KRS-6-48) IP 1mg/kg 1 10 2 20 3 13 14 0 IP 2 mg/kg 1 8 2 20 3 10 13 0 IP 4 mg/kg 1 102 8 3 9 9 31 IP 8 mg/kg 1 12 2 4 3 5 7 46 IP 16 mg/kg 1 1 2 13 3 4 6 54IP 32 mg/kg 1 0 2 1 3 1 1 92 IP 64 mg/kg 1 0 2 0 3 0 0 100 IP 128 mg/kg1 0 2 0 3 0 0 100 Morphine.HCl IP 3 mg/kg 1 0 2 0 3 0 100

Example 13 Analgesic Activity of KRS-6-41, KRS-6-51, and KRS-6-71

Testing on compounds KRS-6-41, KRS-6-51, and KRS-6-71 was also carriedout under contract by MDS Services—Taiwan Ltd. The study was designed toevaluate the effects of the compounds as analgesics in thephenylquinone-induced writhing assay described in detail in Example 10(Siegmund et al, 1957).

In each case, a serial 2-fold dosage variance was used in the test, from128 mg/kg to 1 mg/kg (8 doses in total). Groups of 3 male or female ICRmice weighing 22±2 g were employed. Variant doses (1, 2, 4, 8, 16, 32,64 and 128 mg/kg) of test substances were administered intraperitoneally(IP). A vehicle of 2% Tween 80 in 0.9% NaCl was used for theintraperitoneal injection. The control group received vehicle alone.Phenylquinone (PQ) at dose of 2 mg/kg was injected intraperitoneally 30minutes (IP) after test substance, and the number of writhes exhibitedduring the following 5-10 minute period was recorded. A reduction in thenumber of writhes by 50 percent or more (≧50%) relative to thevehicle-treated group indicated possible analgesic activity.

KRS-6-41

After administration by intraperitoneal injection, a moderate level ofinhibition of writhing in the mice was found for KRS-6-41 at doses of32, 16, 8 and 4 mg/kg. These results are summarised in Table 2. At thehigher doses of 128 mg/kg, 3 of 3 test animals died, and at 64 mg/kg 1of 3 test animals died. None exhibited Straub tail behaviour, whereas 2of 3 test animals exhibited Straub tail behaviour with doses of 3 mg/kgof morphine HCl. This indicates that KRS-6-41 should exhibit a moderateanalgesic effect without a central effect on the central nervous system.

KRS-6-51

After administration by intraperitoneal injection, significant activitywas found for KRS-6-51 at doses of 64 and 32 mg/kg. These results aresummarised in Table 3. At doses of 128 mg/kg 21 of the 3 test animalsdied within 15 minutes, and 2 of the 3 test animals exhibited tremorsand edema. None of the test animals exhibited Straub tail behaviour,thus indicating that KRS-6-51 is able to exert an analgesic effectwithout a central effect on the central nervous system. Morphine-HCl, at3 mg/kg produced Straub tail phenomenon in 2 of 3 test animals. KRS-6-51accordingly compared well against morphine-HCl.

KRS-6-71

After administration by intraperitoneal injection, significant activitywas found for KRS-6-71 at doses of 128, 64, 32, 16, 8 and 4 mg/kg. Theseresults are summarised in Table 4. None of the test animals exhibitedStraub tail behaviour, thus indicating that KRS-6-71 is able to exert ananalgesic effect without a central effect on the central nervous system.Morphine-HCl, at 3 mg/kg produced Straub tail phenomenon in 2 of 3 testanimals. KRS-6-51 accordingly compared very well against morphine-HCl.TABLE 2 Analgesia in the Phenylquinone Writhing Model-KRS-6-41 Number ofWrithings Treatment Route Dose N Individual Average % Inhibition VehicleIP 10 ml/kg 1 17 2% Tween 80/0.9% NaCl 2 10 3 12 13 — KRS-6-41 IP 1mg/kg 1 12 2 15 3 14 14 0 IP 2 mg/kg 1 14 2 6 3 22 14 0 IP 4 mg/kg 1 142 8 3 15 12 8 IP 8 mg/kg 1 6 2 10 3 14 10 23 IP 16 mg/kg 1 5 2 16 3 6 931 IP 32 mg/kg 1 4 2 10 3 11 8 38 IP 64 mg/kg 1 4 2 14 3 died — — IP 128mg/kg 1 died 2 died 3 died — — Morphine IP 3 mg/kg 1 0 2 0 3 0 0 100

TABLE 3 Analgesia in the Phenylquinone Writhing Model-KRS-6-51 Number ofWrithings Treatment Route Dose N Individual Average % Inhibition VehicleIP 10 ml/kg 1 13 2% Tween 80/0.9% NaCl 2 17 3 15 15 — KRS-6-51 IP 1mg/kg 1 11 2 14 3 12 12 20 IP 2 mg/kg 1 18 2 9 3 7 11 27 IP 4 mg/kg 1 102 13 3 7 10 33 IP 8 mg/kg 1 9 2 8 3 8 8 47 IP 16 mg/kg 1 12 2 4 3 7 8 47IP 32 mg/kg 1 3 2 5 3 7 5 67 IP 64 mg/kg 1 0 2 0 3 0 0 100 IP 128 mg/kg1 died 2 0 3 0 — — Morphine IP 3 mg/kg 1 0 2 0 3 0 0 100

TABLE 4 Analgesia in the Phenylquinone Writhing Model-KRS-6-71 Number ofWrithings Treatment Route Dose N Individual Average % Inhibition VehicleIP 10 ml/kg 1 17 2% Tween 80/0.9% NaCl 2 29 3 22 23 — KRS-6-71 IP 1mg/kg 1 24 2 13 3 18 18 22 IP 2 mg/kg 1 2 2 12 3 18 14 39 IP 4 mg/kg 116 2 16 3 2 11 52 IP 8 mg/kg 1 0 2 18 3 15 11 52 IP 16 mg/kg 1 13 2 0 703 8 7 IP 32 mg/kg 1 6 2 0 3 15 7 70 IP 64 mg/kg 1 0 2 3 3 0 1 96 IP 128mg/kg 1 0 2 0 3 0 0 100 Morphine IP 3 mg/kg 1 0 2 0 3 0 0 100

Example 14 Analgesic Activity of KRS-6-98

Testing of compound KRS-6-98 was carried out under contract by MDSPharma Services—Taiwan. The study was essentially the same as that setout in Examples 12 and 13, and was designed to evaluate the effect ofthe compound as an analgesic in the phenylquinone-induced writhing assaydescribed in detail in Example 10 (Siegmund et al, 1957).

A serial two-fold dosage variance was used in the test, from 128 mg/kgto 1 mg/kg (8 doses in total). Twenty six groups of 3 male or female ICRmice weighing 22±2 g were employed. The variant doses of the testsubstance were administered intraperitoneally (IP). A vehicle of 2%Tween 80 in 0.9% NaCl was used for the intraperitoneal injection. Thecontrol group received the vehicle alone. Phenylquinone (PQ) at a doseof 2 mg/kg was injected intraperitoneally 30 minutes (IP) after the testsubstance, and the number of writhes exhibited during the following10-15 minute period was recorded. A reduction of the number of writhesby 50% or more (≧50%) relative to the vehicle-treated group indicate apossible analgesic activity.

For KRS-6-98, significant activity was found at all dose levels from 128down to 2 mg/kg. These results are summarised in Table 5. Straub tailbehaviour in the test animals was not reported, thus indicating thatKRS-6-98 is able to exert an analgesic effect without a central effecton the central nervous system. In view of the morphine-HCL testsreported in relation to other compounds of the invention set out inExample 13, which produced Straub tail phenomenon, this compoundcompared very well against morphine-HCL. TABLE 5 Analgesia in thePhenylquinone Writhing Model-KRS-6-98 Number of Writhings TreatmentRoute Dose N Individual Average % Inhibition Vehicle IP 10 ml/kg 1 15 2%Tween 80/0.9% NaCl 2 20 3 18 18 — KRS-6-98 IP 1 mg/kg 1 12 2 10 3 8 1044 IP 2 mg/kg 1 7 2 6 3 7 7 61 IP 4 mg/kg 1 10 2 7 3 4 7 61 IP 8 mg/kg 16 2 7 3 2 5 72 IP 16 mg/kg 1 3 2 6 3 4 4 78 IP 32 mg/kg 1 0 2 0 3 0 0100 IP 64 mg/kg 1 0 2 0 3 0 0 100 IP 128 mg/kg 1 0 2 0 3 0 0 100

Example 15 In Vitro Opiate Receptor Binding Assays

To characterise the target specificity of the compounds, KRS-6-41,KRS-6-48 and KRS-6-51 were tested at a concentration of 10 μM for theirability to inhibit the binding of a radioligand to human δ-, κ-, orμ-opiate receptors in vitro using commercially available assays (MDSPharma Services; assay catalogue numbers 260110, 260210 and 260410respectively).

The results of these assays are presented below.

Percentage Inhibition of Radioligand Binding to Human Opioid ReceptorsIn Vitro by Test Compounds (10 μM)

Test compound KRS-6-41 KRS-6-48 KRS-6-51 δ-opiate 68 29 37 receptorκ-opiate 58 48 54 receptor μ-opiate 97 97 97 receptor

It will be apparent to the person skilled in the art that while theinvention has been described in some detail for the purposes of clarityand understanding, various modifications and alterations to theembodiments and methods described herein may be made without departingfrom the scope of the inventive concept disclosed in this specification.

References cited herein and below and are incorporated herein by thisreference. The discussion of the references states what their authorsassert, and the applicants reserve the right to challenge the accuracyand pertinency of the cited documents. It will be clearly understoodthat, although a number of prior art publications are referred toherein, this reference does not constitute an admission that any ofthese documents forms part of the common general knowledge in the art,in Australia or in any other country.

REFERENCES

-   D'Amour, F. E. and Smith, D. L. A method for determining loss of    pain sensation. J. Pharmacol. Exp. Ther. 72: 74-79, 1941.-   Sandler, S. R., Karo W. Imidates in Organic Chemistry; Academic    Press, New York, 1972, Chapter 8, vol 3 pages 268-300.-   Siegmund, E., Cadmus, R. and Lu, G. A method for evaluating both    non-narcotic and narcotic analgesics. Proc. Soc. Exp. Biol. Med. 95,    729-731, 1957.

1. A compound of formula I

in which YN is a morphine-like opioid radical; X is—a direct bond, asubstituted or unsubstituted, branched, straight-chained or cyclicalkylene having from 1 to 6 carbon atoms, optionally containing one ortwo heteroatoms in the alkyl chain, or an optionally substituted,branched or straight-chained alkenylene having from 4 to 10 carbonatoms; R and R′ are independently hydrogen, alkyl, substituted alkyl,alkene, substituted alkene, alkyne, substituted alkyne, aryl,substituted aryl, heterocycle, substituted heterocycle or cyano; and nis 0 when X is said direct bond, or n is 1 when X is said alkylene oralkenylene; or a pharmaceutically acceptable salt, hydrate, solvate,pharmaceutically acceptable derivative, pro-drug, tautomer and/or isomerthereof.
 2. The compound of claim 1, wherein R is H, alkyl, phenyl,substituted phenyl, heterocycle or substituted heterocycle.
 3. Thecompound of claim 1, wherein R′ is H, alkyl, substituted alkyl, phenyl,substituted phenyl, heterocycle or substituted heterocycle.
 4. Thecompound of claim 1, wherein at least one of R and R′ is not H.
 5. Thecompound of claim 4, wherein R′ is not H.
 6. The compound of claim 1,wherein the heterocycle or substituted heterocycle is heteroaromatic orsubstituted heteroaromatic, respectively.
 7. The compound of claim 1,wherein the substituent on the aryl or heteroaryl group is a C₁₋₆ alkylgroup, haloalkyl, hydroxy, amino, alkoxy, haloalkoxy, cyano, nitro,alkylthio, thiol, a salt or ester of a phosphorous-containing acid orhalo.
 8. The compound of claim 1, wherein one or both of R and R′ issubstituted, and wherein the substituent or substituents are selectedfrom aryl, substituted aryl, heteroaromatic, substituted heteroaromatic,haloalkyl, hydroxy, amino, alkoxy, haloalkoxy, nitro, alkylthio, thiol,cyano and halo.
 9. The compound of claim 1, wherein R′ is aryl or alkylsubstituted with aryl, in which the aryl group is optionallysubstituted.
 10. The compound of claim 9, wherein said aryl group issubstituted by one or more substituents selected from alkyl, halo,alkoxy, hydroxy, nitro, cyano, a salt or ester of aphosphorous-containing acid and alkyl thio.
 11. The compound of claim 1,wherein X is alkylene and n is
 1. 12. The compound of claim 1, whereinthe radical YN— is a radical of Formula II or Formula III:

wherein: R^(a) is H, C₁₋₄ alkyl, C₁₋₄ alkanoyl, C₁₋₄carboxyalkyl, or anO-protecting group; R^(b) is H, OH, protected hydroxy, C₁₋₄alkanoyloxyor C₁₋₄alkoxy; or, when C6 does not have a double bond to C7, and doesnot have an endoetheno or endoethano bridge to C14, R^(b) may be ═O or═CH₂; R^(c) is H, OH or protected hydroxy; R^(d) is H or C₁₋₄ alkyl;R^(e) is H, CN, C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl, C₂₋₈ alkenyl,

in which R^(f) is H, alkyl, aryl, or alkaryl, and R^(g) is C₁₋₈ alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, each of these three groups being optionallysubstituted by aryl, or R^(g) is substituted aryl (the substituent(s) onthe aryl group being chosen from halo, alkyl, C₁₋₄alkoxy, haloalkyl),tetrahydrofuranyl, C₁₋₄ alkoxy; wherein the oxygen between C4 and C5 mayor may not be present, as represented by the broken lines; wherein thebrackets around the group between C6 and C14 represents that the groupmay or may not be present, and when present the group may be anendoetheno or an endoethano bridge, as represented by the broken line;and wherein the dashed line between C6, C7, C8 and C14 represents thatthere is or are either zero, one or two double bonds, with the onedouble bond being either between C6 and C7, or C7 and C8, and the twodouble bonds being between C6 and C7, and C8 and C14;

wherein R^(h) is H or C₁₋₄ alkyl; R^(i) is H, OH, C₁₋₄ alkanoyl orC₁₋₄alkyl; R^(j) is H, OH, C₁₋₄ alkoxy, C₁₋₄ alkanoyl, C₁₋₄ alkanoyloxy;C₁₋₄ carboxyalkyloxy or protected hydroxy; and R^(k) is H, OH, orprotected hydroxy; and wherein the two dashed lines represent that thetwo bonds may be both present or both absent.
 13. The compound of claim12, wherein the radical YN— is a radical of formula II.
 14. The compoundof claim 12, wherein the radical YN— is a radical of a compound selectedfrom the group consisting of morphine, codeine, heroin, ethylmorphine,O-carboxymethylmorphine, O-acetylmorphine, hydrocodone, hydromorphone,oxymorphone, oxycodone, dihydrocodeine, thebaine, metopon, etorphine,acetorphine, ketobemidone, ethoheptazine, diprenorphine (M5050),buprenorphine, phenomorphan, levorphanol, pentazocine, eptazocine,metazocine, dihydroetorphine and dihydroacetorphine.
 15. The compound ofclaim 12, wherein the radical YN— is a radical of morphine, codeine,buprenorphine or diprenorphine.
 16. A compound selected from the groupconsisting of:

wherein Z is selected from alkyl, halo, alkoxy, hydroxy, cyano, nitro,alkyl thio, or a pharmaceutically acceptable salt, hydrate, solvate,pre-drug, tautomer and/or isomer thereof.
 17. A process for thepreparation of a compound of formula I as defined in claim 1 comprisingthe step of reacting a precursor for the radical YN— or YN—X—NH— with aprecursor for the radical

in which YN—, X, R, R′, R″ and n are as defined in claim
 1. 18. Theprocess of claim 17, wherein the process includes the step of reactingYN—H or YN—X—NH₂ with a compound of formula

in which R and R′ are as defined in claim 1, and R′ is alkyl,substituted alkyl, aryl or substituted aryl, to form a compound ofFormula I.
 19. A pharmaceutical or veterinary composition comprising acompound of claim 1, and of a pharmaceutically or veterinarilyacceptable carrier.
 20. A method of treatment and/or prophylaxis of acondition or symptom that is inhibited, reduced or alleviated by opioidreceptor activation, comprising administering a therapeuticallyeffective amount of the compound of claim 1 to a subject in needthereof.
 21. The method of claim 20, wherein the method involves thetreatment and/or prophylaxis of pain in the peripheral nervous systemwith comparably less or no activity on the central nervous system.
 22. Amethod of inducing analgesia, comprising the step of administering aneffective amount of a compound of claim 1 to a subject in need of suchtreatment. 23-26. (canceled)
 27. A method of reducing the centralnervous system activity of a morphine-like opioid, comprising the stepof linking the nitrogen atom of the morphine-like opioid to the radical

in which X, R, R′ and n are as defined in claim 1.